Bispecific T cell receptor molecules designed to wipe out HIV-infected T cells offer glimpses of a cure.
The first T cell receptor (TCR) therapeutic designed to eliminate cells harboring latent HIV-1 has passed initial clinical tests. A bispecific immunotherapy made by Immunocore could eliminate CD4+ cells that are persistently infected with HIV, known as ‘reservoirs’. The aim is to suppress HIV replication and control the virus to achieve a ‘functional cure’ in the absence of anti-retroviral therapy (ART), which would represent a game-changing alternative for the millions of people living with HIV.
HIV-1 particles (pink) bud from inside a T cell.
Credit: IMAGO/NIH-NIAID / IMAGE POINT FR / BSIP
“Although ART enables people with HIV to live a normal life, patients consistently tell us they want to feel cured,” says Kimberly Smith, Head of Research and Development for ViiV Healthcare.
The CD4+ T cell reservoir is the main reason why countless attempts to eradicate the HIV-1 virus from the body have failed. Within these immune cells, the virus remains latent, resisting ART and evading immune recognition. Therapies aimed at a functional cure now seek to clear those reservoir cells where the virus persists. “The cure space has reached an inflection point,” says Michel Nussenzweig, Howard Hugues Medical Institute, Rockefeller University. Thanks to a deeper understanding of how the reservoir becomes established and is maintained, he remains optimistic about new strategies that specifically target these cells.
Antibody therapies work by targeting surface antigens. They offer astounding antigen specificity, but their scope is limited to targeting proteins on cell membranes or in extracellular spaces. In contrast, TCRs and TCR-based therapies can recognize intracellular proteins too, opening up a whole new constellation of targets beyond what antibodies can tackle. In particular, it ushers in the possibility of applying the technology to seeking out viruses and other infectious agents that persist by permanently integrating into the host genome and remain hidden from the immune system, leading to chronic infections.
Immunocore uses a soluble bispecific TCR that combines the exquisite specificity of TCRs with the cell-killing prowess of a CD3 antibody domains. Lucy Dorrell, director in Infectious Diseases Research and Clinical Development at Immunocore, says these agents are “an evolution of antibody therapy.”
Immunocore already has clinical proof with the same platform in oncology. The company’s first-in-class Kimmtrak (tebentafusp-tebn) was approved in 2022 to treat patients with HLA-A*02:01-positive uveal melanoma.
The company has now engineered an HIV-specific ImmTAV (GAG×CD3) that redirects effector cells to eliminate HIV-infected cells presenting a specific HLA-bound Gag-derived viral peptide. The TCR-based bispecifics, called ImmTAX molecules, have two arms: a high-affinity TCR that detects a viral peptide epitope presented on the surface of target cells — even at very low levels — and an antibody arm that binds to CD3 to recruit and activate immune T cells, serving to redirect the non-specific T cells to the target and killing cells infected with HIV. With the ImmTAX molecules’ assistance, the recruited T cells can detect even low copy numbers of viral peptides in infected immune cells. People positive for HIV have been treated with single intravenous infusions of the bispecific TCR therapeutic IMC-M113V. So far, doses ≤15 μg are well tolerated and are associated with an increase in serum interleukin-6, an indicator of biological activity consistent with the agent’s action. An ascending dose study is underway. “We envisage the drug being given with ART but for a finite period of time,” Dorrell says, until the risk of viral replication is minimal.
Over 30 million people with HIV rely on ART pills or long-acting injectable regimens to keep the disease in check, and expect to have to do this for the rest of their lives. ART has dramatically improved the lives of people with HIV, transforming the infection from fatal disease to a manageable condition. With an effective regimen of three drugs — two nucleoside reverse transcriptase inhibitors and either an integrase or protease or non-nucleotide reverse transcriptase inhibitor — people with HIV can stay healthy and avoid passing on the virus.
But although the ART drug combination reduces HIV in blood to undetectable levels, the viral load rebounds within a few weeks if ART should stop. An interruption in supply due to war or climate disasters could rapidly prompt a resurgence in new cases and deaths. Drug resistance to ART is also a risk, as the virus is prone to mutate, and there is potential for drug–drug interactions that could lead to treatment failure. People also wish to avoid the stigma associated with life-long medication. “We need to find a better way of treating HIV,” says Sarah Fidler, a clinical immunologist at Imperial College London.
Some people have successfully cleared the virus for good. The first time was in 2006, following a bone marrow transplant to treat acute myeloid leukemia. Since then, at least seven other people with HIV have had the virus eradicated from their bodies after receiving a bone marrow transplant as part of a cancer treatment. The transplanted stem cells had a 32-bp deletion in just one or in both copies of the chemokine CC-motif receptor 5 (CCR5) gene, which encodes a protein that is a key entry point for HIV to infect immune cells. As Fidler points out, this strategy is expensive, high risk and impractical for the global population of people living with the virus. Nevertheless, it demonstrates that a ‘sterilizing’ cure is possible.
Other insights leading to a cure could come from so-called ‘elite’ controllers, who, despite being infected, maintain an undetectable viral load without ART. This spontaneous damping down of the virus, present in <1% of people living with HIV, could be associated with enhanced immune function or related to the site where the virus integrates into the host’s genome.
“The virus can insert itself in deep, dark places of the genome,” says Nussenzweig, where it is effectively shut off and unlikely to be reactivated. The area close to the centromere, the region of the chromosome that connects the sister chromatids, is one such ‘transcriptional desert’ where the virus remains silenced. “We still don’t know if the site of virus integration is random or immune mediated,” Fidler notes. That elite controllers exist at all indicates that it may not be necessary to completely eliminate HIV for a person to lead a healthy, medication-free life without passing on the virus to others
To tackle the reservoirs, scientists first need to understand how these HIV-infected CD4+ T cells behave. The majority are dynamic clones where virus protein expression changes over time, often at levels low enough not to kill all the cells but enough to cause a rebound if ART is discontinued. In addition to Immunocore’s bispecific, several other strategies are in development aimed at disabling and killing these infected cells (Table 1).
Some companies engineer vaccines or immunogens to rouse the immune system to produce anti-HIV antibodies. Unfortunately, the responses recorded so far have been neither strong nor long-lasting. But many are continuing to test broadly neutralizing antibodies — those aimed at neutralizing multiple HIV-1 viral strains by targeting conserved viral epitopes. These have protected non-human primates from infection. Dozens of clinical trails are underway to determine whether the same can apply in humans. In the phase 2 RIO trial, 72 people recently infected with HIV in the UK and US received a combination of two long-acting broadly neutralizing antibodies, 3BNC117-LS and 10-1074-LS. The antibodies target the virus’s binding site on the CD4 receptor and the V3 loop of the HIV envelope protein gp120. The trial will assess whether this antibody combination can stop viral rebound after ART interruption. Results are expected later this year. “[Broadly neutralizing antibodies] may not eliminate the virus from the body, but I feel they are likely to be part of the solution,” says Nussenzweig, who is leading the RIO trial.
Another strategy to reduce the HIV reservoir, referred to as ‘kick and kill’, involves using latency-reversing agents (LRAs) to activate transcription of the virus and a vaccine to stimulate T cell immunity. Histone deacetylase inhibitors such as vorinostat force HIV transcription and prime reservoir cells for destruction by the immune system. These agents, however, are not specific for HIV and can be toxic. Results of the RIVER trial in the UK showed that ART plus vorinostat and a vaccine did not reduce the reservoir size compared to ART alone. “The concept is probably correct, but we don’t have the right tools to do the job,” says Fidler, who was involved in the trial.
Gene therapies are another powerful tool to arm the immune system against HIV. One type of gene therapy in early-stage trials is testing autologous anti-HIV T cell therapies. In vivo gene therapies, which avoid the need to genetically manipulate and expand patients’ immune cells, could hold sway. These could work by directly reducing the expression of CCR5 in T cells or excising HIV genes from infected cells. Enthusiasm for such approaches has grown following the approval of the CRISPR–Cas9-based therapy Casgevy (exagamglogene autotemcel) for sickle cell disease and β-thalassemia. The same approach that successfully repairs the faulty hemoglobin genes in blood stem cells of these patients could be applied to CCR5 in people infected with HIV.
In China, gene editing has been used to knockout the CCR5 gene in the hematopoietic stem cells of patients undergoing allogeneic stem cell transplantation for blood cancers. Results in one patient showed that the cells carrying the ablated CCR5 persisted for more than 19 months without gene-editing-related adverse events. However, the percentage of these cells was too small to prevent an increase in viral load when ART is interrupted. Also, in 2018, He Jiankui broke national regulations and attracted worldwide condemnation when he chose to disable the CCR5 gene in the first ‘CRISPR babies’ to protect them from HIV infection.
Instead, Excision BioTherapeutics is applying gene editing to cut out HIV genes integrated into the genomes of CD4 T cells and prevent production of new virus. The EBT-101 therapy simultaneously targets three sites within the HIV genome. Early-stage clinical trials have shown that, when administered as a single intravenous infusion via an adeno-associated vector, EBT-101 is safe and well tolerated. Unfortunately, it did not delay HIV rebound in three participants when they stopped ART. “We still have a lot to learn about ways to optimize this treatment and deliver it in a way that it reaches enough cells to have an effect,” says Rachel Presti, principal investigator of the phase 1/2 trial, which was based in Washington University, St. Louis, Missouri.
Perhaps the greatest difficulty in finding a cure for HIV is that people on ART are not sick. The risk/benefit profile of any intervention aimed at safely stopping ART is very different from that of patients with limited treatment options. The acceptance of severe side effects is understandably much lower in people living with HIV. “We have to take a very careful approach,” says Immunocore’s Dorrell about the IMC-M113V trial. Because the agent is designed to elicit a potent immune response against a tiny amount of virus, it will be crucial to find a dosing regimen that is effective at destroying reservoir cells without causing cytokine release syndrome, a potential side effect with Kimmtrak.
When can drug developers claim success? It is still unclear how many reservoir cells have to be eliminated to avoid viral rebound. Measuring such cells in people with HIV on ART is problematic. Most methods measure total HIV DNA, replication-competent DNA or HIV RNA in peripheral blood, potentially missing reservoir cells hidden in tissues. “If you can’t find reservoir cells, is it because they are not there or because your assay is not sensitive enough?” says Fidler.
Improving ART formulation could be a much easier way to achieve long-term remission without daily pills. ViiV Healthcare’s slow-release ART Cabenuva (cabotegravir and rilpivirine) was approved in 2021 and is administered as intramuscular injections every two months. The company is working to further increase the molecules’ half-lives to enable injections two to three times a year. ViiV Healthcare has also developed the extended-release injectable Apretude (cabotegravir) to prevent HIV infection. A study in cis-gendered women in sub-Saharan Africa showed that it was nine times more effective at reducing HIV transmission than daily preexposure prophylaxis pills.
Despite these successes, broadly neutralizing antibodies and LRAs are still high on the agenda. A functional cure (or long-term remission) will most likely require combined approaches. The remaining task is to ensure that bispecific TCRs, LRAs, broadly neutralizing antibodies and gene therapies are affordable and accessible to all. As Presti notes, if everyone infected with the virus was on ART and those at risk took preventative treatment, transmission would be stopped, and “that would be kind of a cure.”
